Substituted gamma lactams as therapeutic agents

ABSTRACT

A compound comprising 
                         
or a pharmaceutically acceptable salt thereof, or a prodrug thereof is disclosed herein. Y, A, and B are as described herein.
 
     Methods, compositions, and medicaments related to these compounds are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

This application is based on, and claims priority under 35 U.S.C. § 120to U.S. Provisional Patent Application No. 60/783,979, filed on Mar. 20,2006, and which is incorporated herein by reference.

DESCRIPTION OF RELATED ART

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical β-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Certain eicosanoids and their derivatives are currently commerciallyavailable for use in glaucoma management. Eicosanoids and derivativesinclude numerous biologically important compounds such as prostaglandinsand their derivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

Various types of prostaglandins are known, depending on the structureand substituents carried on the alicyclic ring of the prostanoic acidskeleton. Further classification is based on the number of unsaturatedbonds in the side chain indicated by numerical subscripts after thegeneric type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [e.g. prostaglandin F_(2α)(PGF_(2β))].

Prostaglandin EP₂ selective agonists are believed to have severalmedical uses. For example, U.S. Pat. No. 6,437,146 teaches the use ofprostaglandin EP₂ selective agonists “for treating or preventinginflammation and pain in joint and muscle (e.g., rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenilearthritis, etc.), inflammatory skin condition (e.g., sunburn, burns,eczema, dermatitis, etc.), inflammatory eye condition (e.g.,conjunctivitis, etc.), lung disorder in which inflammation is involved(e.g., asthma, bronchitis, pigeon fancier's disease, farmer's lung,etc.), condition of the gastrointestinal tract associated withinflammation (e.g., aphthous ulcer, Crohn's disease, atrophic gastritis,gastritis varialoforme, ulcerative colitis, coeliac disease, regionalileitis, irritable bowel syndrome, etc.), gingivitis, inflammation, painand tumescence after operation or injury, pyrexia, pain and otherconditions associated with inflammation, allergic disease, systemiclupus erythematosus, scleroderma, polymyositis, tendinitis, bursitis,periarteritis nodose, rheumatic fever, Sjogren's syndrome, Behcetdisease, thyroiditis, type I diabetes, diabetic complication (diabeticmicroangiopathy, diabetic retinopathy, diabetic nephropathy, etc.),nephrotic syndrome, aplastic anemia, myasthenia gravis, uveitis contactdermatitis, psoriasis, Kawasaki disease, sarcoidosis, Hodgkin's disease,Alzheimers disease, kidney dysfunction (nephritis, nephritic syndrome,etc.), liver dysfunction (hepatitis, cirrhosis, etc.), gastrointestinaldysfunction (diarrhea, inflammatory bowel disease, etc.) shock, bonedisease characterized by abnormal bone metabolism such as osteoporosis(especially, postmenopausal osteoporosis), hypercalcemia,hyperparathyroidism, Paget's bone diseases, osteolysis, hypercalcemia ofmalignancy with or without bone metastases, rheumatoid arthritis,periodontitis, osteoarthritis, ostealgia, osteopenia, cancer cachexia,calculosis, lithiasis (especially, urolithiasis), solid carcinoma,mesangial proliferative glomerulonephritis, edema (e.g. cardiac edema,cerebral edema, etc.), hypertension such as malignant hypertension orthe like, premenstrual tension, urinary calculus, oliguria such as theone caused by acute or chronic failure, hyperphosphaturia, or the like.”

U.S. Pat. No. 6,710,072 teaches the use of EP2 agonists for thetreatment or prevention of “osteoporosis, constipation, renal disorders,sexual dysfunction, baldness, diabetes, cancer and in disorder of immuneregulation . . . various pathophysiological diseases including acutemyocardial infarction, vascular thrombosis, hypertension, pulmonaryhypertension, ischemic heart disease, congestive heart failure, andangina pectoris.”

DESCRIPTION OF THE INVENTION

A compound is disclosed herein comprising

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein Y is an organic acid functional group, or an amide or ester    thereof comprising up to 12 carbon atoms; or Y is hydroxymethyl or    an ether thereof comprising up to 12 carbon atoms; or Y is a    tetrazolyl functional group;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O; and-   B is aryl or heteroaryl.

Y is an organic acid functional group, or an amide or ester thereofcomprising up to 12 carbon atoms; or Y is hydroxymethyl or an etherthereof comprising up to 12 carbon atoms; or Y is a tetrazolylfunctional group.

An organic acid functional group is an acidic functional group on anorganic molecule. While not intending to be limiting, organic acidfunctional groups may comprise an oxide of carbon, sulfur, orphosphorous. Thus, while not intending to limit the scope of theinvention in any way, in certain compounds Y is a carboxylic acid,sulfonic acid, or phosphonic acid functional group, i.e. one of thestructures shown below.

Salts of any of these acids of any pharmaceutically acceptable form arealso contemplated.

Additionally, an amide or ester of one of the organic acids shown abovecomprising up to 12 carbon atoms is also contemplated. In an ester, ahydrocarbyl moiety replaces a hydrogen atom of an acid such as in acarboxylic acid ester, e.g. CO₂Me, CO₂Et, etc.

In an amide, an amine group replaces an OH of the acid. Examples ofamides include CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂, and CONH(CH₂CH₂OH)where R² is independently H, C₁-C₆ alkyl, phenyl, or biphenyl. Moietiessuch as CONHSO₂R² are also amides of the carboxylic acid notwithstandingthe fact that they may also be considered to be amides of the sulfonicacid R²—SO₃H.

While not intending to limit the scope of the invention in any way, Ymay also be hydroxymethyl or an ether thereof comprising up to 12 carbonatoms. Thus, compounds having a structure shown below are possible.

Additionally, ethers of these compounds are also possible. An ether is afunctional group wherein a hydrogen of an hydroxyl is replaced bycarbon, e.g., Y is CH₂OCH₃, CH₂OCH₂CH₃, etc.

Finally, while not intending to limit the scope of the invention in anyway, Y may be a tetrazolyl functional group, such as compounds having astructure according to the formula below.

An unsubstituted tetrazolyl functional group has two tautomeric forms,which can rapidly interconvert in aqueous or biological media, and arethus equivalent to one another. These tautomers are shown below.

Additionally, if R² is C₁-C₆ alkyl, phenyl, or biphenyl, other isomericforms of the tetrazolyl functional group such as the one shown below arealso possible, unsubstituted and hydrocarbyl substituted tetrazolyl upto C₁₂ are considered to be within the scope of the term “tetrazolyl.”

While not intending to limit the scope of the invention in any way, inone embodiment, Y is selected from the group consisting of CO₂(R²),CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂, CONH(CH₂CH₂OH), CH₂OH, P(O)(OH)₂,CONHSO₂R², SO₂N(R²)₂, SO₂NHR², and tetrazolyl-R²; wherein R² isindependently H, C₁-C₆ alkyl, phenyl, or biphenyl.

In another embodiment Y is not CONH-phenyl or CONH-cyclohexyl.

In relation to the identity of A disclosed in the chemical structurespresented herein, A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be substituted with Sor O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene orheterointerarylene, the sum of m and o is from 1 to 4, and wherein oneCH₂ may be substituted with S or O.

While not intending to be limiting, A may be —(CH₂)₆—, cis—CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—.

Alternatively, A may be a group which is related to one of these threemoieties in that any carbon is substituted with S and/or O. For example,while not intending to limit the scope of the invention in any way, Amay be an S substituted moiety such as one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may be an O substituted moiety such as one of thefollowing or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may have both an O and an S substituted into the chain,such as one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, in certain embodiments A is —(CH₂)_(m)—Ar—(CH₂)_(o)— whereinAr is interarylene or heterointerarylene, the sum of m and o is from 1to 4, and wherein one CH₂ may be substituted with S or O. In otherwords, while not intending to limit the scope of the invention in anyway,

-   in one embodiment A comprises from 1 to 4 CH₂ moieties and Ar, e.g.    —CH₂—Ar—, —(CH₂)₂—Ar—, —CH₂—Ar—CH₂—, —CH₂—Ar—(CH₂)₂—,    —(CH₂)₂—Ar—(CH₂)₂—, and the like; or-   A comprises O, from 0 to 3 CH₂ moieties, and Ar, e.g., —O—Ar—, 0    Ar—CH₂—O—, —O—Ar—(CH₂)₂—, —O—CH₂—Ar—, —O—CH₂—Ar—(CH₂)₂, and the    like; or-   A comprises S, from 0 to 3 CH₂ moieties, and Ar, e.g., —S—Ar—,    Ar—CH₂—S—, —S—Ar—(CH₂)₂—, —S—CH₂—Ar—, —S—CH₂—Ar—(CH₂)₂,    —(CH₂)₂—S—Ar, and the like.    In another embodiment, the sum of m and o is from 2 to 4 wherein one    CH₂ may be substituted with S or O.

In another embodiment, the sum of m and o is 3 wherein one CH₂ may besubstituted with S or O.

In another embodiment, the sum of m and o is 2 wherein one CH₂ may besubstituted with S or O.

In another embodiment, the sum of m and o is 4 wherein one CH₂ may besubstituted with S or O.

Interarylene or heterointerarylene refers to an aryl ring or ring systemor a heteroaryl ring or ring system which connects two other parts of amolecule, i.e. the two parts are bonded to the ring in two distinct ringpositions.

Interarylene or heterointerarylene may be substituted or unsubstituted.Unsubstituted interarylene or heterointerarylene has no substituentsother than the two parts of the molecule it connects. Substitutedinterarylene or heterointerarylene has one or more substitutents inaddition to the two parts of the molecule it connects.

In one embodiment, Ar is substituted or unsubstituted interphenylene,interthienylene, interfurylene, interpyridinylene, interoxazolylene, andinterthiazolylene. In another embodiment Ar is interphenylene (Ph). Inanother embodiment A is —(CH₂)₂-Ph-. While not intending to limit scopeof the invention in any way, substituents may have 4 or less heavyatoms, or in other words, non hydrogen atoms. Any number of hydrogenatoms required for a particular substituent will also be included. Thus,the substituent may be

-   hydrocarbyl i.e. a moiety consisting of only carbon and hydrogen    such as alkyl, having up to 4 carbon atoms, including alkyl up to    C₄, alkenyl, alkynyl, and the like;-   hydrocarbyloxy up to C₃;-   CF₃;-   halo, such as F, Cl, or Br;-   hydroxyl;-   NH₂ and alkylamine functional groups up to C₃;-   other N or S containing substituents;-   and the like.

Substituted interarylene or interheteroarylene may have one or moresubstituents, up to as many as the ring or ring system will bear, andthe substituents may be the same or different. Thus, for example, aninterarylene ring or interheteroarylene ring may be substituted withchloro and methyl; methyl, OH, and F; CN, NO₂, and ethyl; and the likeincluding any conceivable substituent or combination of substituentpossible in light of this disclosure.

In one embodiment A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar isinterphenylene, the sum of m and o is from 1 to 3, and wherein one CH₂may be substituted with S or O.

In another embodiment A is —CH₂—Ar—OCH₂—. In another embodiment A is—CH₂—Ar—OCH₂— and Ar is interphenylene. In another embodiment, Ar is 1,3interaryl or interheteroaryl, where Ar attached at the 1 and 3positions, such as when A has the structure shown below.

Other examples of 1,3 interaryl or interheteroaryl are exemplified inthe following examples of A-Y.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, orCH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be substituted with S orO; or A is —(CH₂)₂-Ph- wherein one CH₂ may be substituted with S or O.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, orCH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be substituted with S orO; or A is —(CH₂)₂-Ph-.

In another embodiment A is not —(CH₂)₆—.

In other embodiments, A has one of the following structures, where Y isattached to the oxazolyl or thiazolyl ring.

In other embodiments A is one of the structures shown below, where Y isattached to the phenyl or heteroaryl ring.

In another embodiment A is —CH₂OCH₂Ar.

In another embodiment A is —CH₂SCH₂Ar.

In another embodiment A is —(CH₂)₃Ar.

In another embodiment A is —CH₂O(CH₂)₄.

In another embodiment A is —CH₂S(CH₂)₄.

In another embodiment A is, —S(CH₂)₃S(CH₂)₂—.

In another embodiment A is, —(CH₂)₄OCH₂—.

In another embodiment A is, cis —CH₂CH═CH—CH₂OCH₂—.

In another embodiment A is, —CH₂CH≡CH—CH₂OCH₂—.

In another embodiment A is, —(CH₂)₂S(CH₂)₃—.

In another embodiment A is, —CH₂-Ph-OCH₂—, wherein Ph is interphenylene.

In another embodiment A is, —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene.

In another embodiment A is, —CH₂—O—(CH₂)₄—.

In another embodiment A is, —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene.

In another embodiment A is, —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene.

B is aryl or heteroaryl.

Aryl is an unsubstituted or substituted aromatic ring or ring systemsuch as phenyl, naphthyl, biphenyl, and the like.

Heteroaryl is aryl having one or more N, O, or S atoms in the ring, i.e.a ring carbon is substituted by N, O, or S. While not intending to belimiting, examples of heteroaryl include unsubstituted or substitutedthienyl, pyridinyl, furyl, benzothienyl, benzofuryl, imidizololyl,indolyl, and the like.

The substituents of aryl or heteroaryl may have up to 12 non-hydrogenatoms each and as many hydrogen atoms as necessary. Thus, while notintending to limit the scope of the invention in any way, thesubstituents may be:

-   hydrocarbyl, i.e. a moiety consisting of only carbon and hydrogen    such as alkyl, alkenyl, alkynyl, and the like, including linear,    branched or cyclic hydrocarbyl, and combinations thereof;-   hydrocarbyloxy, meaning O-hydrocarbyl such as OCH₃, OCH₂CH₃,    O-cyclohexyl, etc, up to 11 carbon atoms;-   other ether substituents such as CH₂OCH₃, (CH₂)₂OCH(CH₃)₂, and the    like;-   thioether substituents including S-hydrocarbyl and other thioether    substituents;-   hydroxyhydrocarbyl, meaning hydrocarbyl-OH such as CH₂OH, C(CH₃)₂OH,    etc, up to 11 carbon atoms;-   nitrogen substituents such as NO₂, CN, and the like, including-   amino, such as NH₂, NH(CH₂CH₃OH), NHCH₃, and the like up to 11    carbon atoms;-   carbonyl substituents, such as CO₂H, ester, amide, and the like;-   halogen, such as chloro, fluoro, bromo, and the like-   fluorocarbyl, such as CF₃, CF₂CF₃, etc.;-   phosphorous substituents, such as PO₃ ²⁻, and the like;-   sulfur substituents, including S-hydrocarbyl, SH, SO₃H,    SO₂-hydrocarbyl, SO₃-hydrocarbyl, and the like.

In certain embodiments, the number of non-hydrogen atoms is 6 or less ina substituent. In other embodiments, the number of non-hydrogen atoms is3 or less in a substituent. In other embodiments, the number ofnon-hydrogen atoms on a substituent is 1.

In certain embodiments, the substituents contain only hydrogen, carbon,oxygen, halogen, nitrogen, and sulfur. In other embodiments, thesubstituents contain only hydrogen, carbon, oxygen, and halogen.

Unless otherwise indicated, references to aryl, heteroaryl, phenyl,thienyl, benzothienyl, and the like are intended to mean both thesubstituted and the unsubstituted moiety.

Substituted aryl or heteroaryl may have one or more substituents, up toas many as the ring or ring system will bear, and the substituents maybe the same or different. Thus, for example, an aryl ring or aheteroaryl ring may be substituted with chloro and methyl; methyl, OH,and F; CN, NO₂, and ethyl; and the like including any conceivablesubstituent or combination of substituent possible in light of thisdisclosure.

Thus, compounds wherein B is any of the above classes or species of arylor heteroaryl are contemplated herein.

Further, while not intending to limit the scope of the invention in anyway, in one embodiment B is phenyl. In another embodiment B ischlorophenyl, meaning phenyl with one or more chloro substituents. Inanother embodiment D is 3,5-dichlorophenyl. In another embodiment B isunsubstituted phenyl. In another embodiment B is alkylphenyl. In anotherembodiment B is t-butylphenyl.

In another embodiment B is not unsubstituted phenyl. In anotherembodiment B is not chlorophenyl. In another embodiment B is notfluorophenyl. In another embodiment B is not dimethylaminophenyl. Inanother embodiment B is not unsubstituted phenyl, chlorophenyl,fluorophenyl, or dimethylaminophenyl.

In another embodiment B is hydroxyalkylphenyl, meaning phenyl with ahydroxyalkyl substitutent such as Ph-C H(OH)C(CH₃)₃.

B can also be any of the groups shown below, where the remainder of themolecule attaches to the phenyl ring. The names of these moieties areshown to the right of the structure.

One compound comprises

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein a dashed line indicates the presence or absence of a bond R    is hydrocarbyl or hydroxyhydrocarbyl having from 1 to 12 carbon    atoms.

Another embodiment comprises

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein a dashed line indicates the presence or absence of a bond;-   R³, R⁴, and R⁵ are independently H or C₁₋₆ alkyl.

As the dashed line indicates the presence or absence of a bond, R⁴ andR⁵ may be two separate moieties. For example, while not intending to belimiting, in one embodiment R⁴ and R⁵ is methyl, and no bond is presentwhere indicated by the dashed line.

For example, a compound according to the formula below

or a pharmaceutically acceptable salt thereof, or a prodrug thereof iscontemplated. Alternatively, while not intending to limit the scope ofthe invention in any way, R⁴ and R⁵ may form a ring. In other words, acompound such as the one shown below is possible, wherein x is from 1 to6.

A pharmaceutically acceptable salt thereof, or a prodrug thereof is alsocontemplated.

Another embodiment comprises

A pharmaceutically acceptable salt thereof, or a prodrug thereof is alsocontemplated.

Other useful compounds comprise

A pharmaceutically acceptable salt thereof, or a prodrug thereof is alsocontemplated.

Other useful examples of compounds comprise

or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Other compounds comprise

or a pharmaceutically acceptable salt thereof, or a prodrug thereof,

-   wherein R⁶ is cycloalkyl comprising from 3 to 10 carbon atoms.

Other compounds comprise

or a pharmaceutically acceptable salt thereof, or a prodrug thereof,

-   wherein R⁷ is linear alkyl comprising from 3 to 7 carbon atoms.

Other compounds comprise

or a pharmaceutically acceptable salt thereof, or a prodrug thereof,

-   wherein X¹ and X² are independently CH, O, or S; and-   R⁷ is linear alkyl comprising from 3 to 7 carbon atoms.

Other compounds comprise

or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Other compounds comprise

or a pharmaceutically acceptable salt thereof, or a prodrug thereof,

-   wherein X¹ and X² are independently CH, O, or S.

Other compounds comprise

or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Other compounds comprise

or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Another useful compound is

or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Another useful compound is

or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

In one embodiment, a compound comprising

is not used, wherein

-   D is phenyl or cyclohexyl; and-   E is unsubstituted phenyl, chlorophenyl, fluorophenyl, or    dimethylaminophenyl.

Another compound comprises

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—.

Another compound comprises

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—.

Another compound comprises

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein a dashed line indicates the presence or absence of a bond;-   R is hydrocarbyl or hydroxyhydrocarbyl having from 1 to 12 carbon    atoms;-   X is CH₂, O, or S; and-   G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—.

Another compound is an N-aryl or N-heteroaryl gamma lactam which isactive at a prostaglandin receptor.

This compound may or may not incorporate any other structural limitationdisclosed herein.

Another compound is an N-aryl or N-heteroaryl gamma lactam which isselectively active at a prostaglandin EP₂ receptor. This compound may ormay not incorporate any other structural limitation disclosed herein.

Another compound is an N-aryl or N-heteroaryl gamma lactam which iseffective at reducing intraocular pressure in a mammal. This compoundmay or may not incorporate any other structural limitation disclosedherein.

The determination of whether a compound is active at a prostaglandinreceptor is well within the ability of a person of ordinary skill in theart. The determination of whether a compound is active at aprostaglandin EP₂ receptor is also well within the ability of a personof ordinary skill in the art. While not intending to limit the scope ofthe invention in any way, one method of making such determinations isalso provided in the examples herein.

The determination of whether a compound is effective at reducingintraocular pressure in a mammal is well within the ability of a personof ordinary skill in the art. While not intending to limit the scope ofthe invention in any way, methods of determining whether a compound iseffective in reducing intraocular pressure are given for a few exemplarymammals herein.

While not intending to limit the scope of the invention in any way,examples of useful compounds are depicted below, and pharmaceuticallyacceptable salts or prodrugs thereof.

In one embodiment A is —S(CH₂)₃S(CH₂)₂— and B is phenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is phenyl.

As mentioned before, phenyl in the above embodiments means substitutedor unsubstituted phenyl unless indicated otherwise.

In one embodiment A is —S(CH₂)₃S(CH₂)₂— and B is (1-hydroxyhexyl)phenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is (1-hydroxyhexyl)phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is(1-hydroxyhexyl)phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is(1-hydroxyhexyl)phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is(1-hydroxyhexyl)phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is (1-hydroxyhexyl)phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is (1-hydroxyhexyl)phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is(1-hydroxyhexyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is (1-hydroxyhexyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is (1-hydroxyhexyl)phenyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is(1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is(1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is(1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is(1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is(1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is (1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is (1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is(1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is (1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is (1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is(1-hydroxy-2-methylpropyl)phenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is(1-hydroxy-2-methylpropyl)phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is(1-hydroxy-2-methylpropyl)phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is(1-hydroxy-2-methylpropyl)phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is(1-hydroxy-2-methylpropyl)phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is (1-hydroxy-2-methylpropyl)phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is (1-hydroxy-2-methylpropyl)phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is(1-hydroxy-2-methylpropyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is (1-hydroxy-2-methylpropyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is (1-hydroxy-2-methylpropyl)phenyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is(hydroxymethyl)phenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is (hydroxymethyl)phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is(hydroxymethyl)phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is(hydroxymethyl)phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is(hydroxymethyl)phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is (hydroxymethyl)phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is (hydroxymethyl)phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is(hydroxymethyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is (hydroxymethyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is (hydroxymethyl)phenyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is[(1-propylcyclobutyl)hydroxymethyl]phenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is[(1-propylcyclobutyl)hydroxymethyl]phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is[(1-propylcyclobutyl)hydroxymethyl]phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is[(1-propylcyclobutyl)hydroxymethyl]phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is[(1-propylcyclobutyl)hydroxymethyl]phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is [(1-propylcyclobutyl)hydroxymethyl]phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is [(1-propylcyclobutyl)hydroxymethyl]phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is[(1-propylcyclobutyl)hydroxymethyl]phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is [(1-propylcyclobutyl)hydroxymethyl]phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is [(1-propylcyclobutyl)hydroxymethyl]phenyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is t-butylphenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is t-butylphenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B ist-butylphenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is t-butylphenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is t-butylphenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is t-butylphenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is t-butylphenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is t-butylphenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is t-butylphenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is t-butylphenyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is(cyclohexylhydroxymethyl)phenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is(cyclohexylhydroxymethyl)phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is(cyclohexylhydroxymethyl)phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is(cyclohexylhydroxymethyl)phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is(cyclohexylhydroxymethyl)phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is (cyclohexylhydroxymethyl)phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is (cyclohexylhydroxymethyl)phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is(cyclohexylhydroxymethyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is (cyclohexylhydroxymethyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is (cyclohexylhydroxymethyl)phenyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is(cyclohexylmethyl)phenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is(cyclohexylmethyl)phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is(cyclohexylmethyl)phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is(cyclohexylmethyl)phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is(cyclohexylmethyl)phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is (cyclohexylmethyl)phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is (cyclohexylmethyl)phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is(cyclohexylmethyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is (cyclohexylmethyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is (cyclohexylmethyl)phenyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is indanyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is indanyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is indanyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is indanyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is indanyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is indanyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is indanyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is indanyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is indanyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is indanyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is indanolyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is indanolyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is indanolyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is indanolyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is indanolyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is indanolyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is indanolyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is indanolyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is indanolyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is indanolyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is indanonyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is indanonyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is indanonyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is indanonyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is indanonyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is indanonyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is indanonyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is indanonyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is indanonyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is indanonyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is(1-hydroxycyclobutyl)phenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is(1-hydroxycyclobutyl)phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is(1-hydroxycyclobutyl)phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is(1-hydroxycyclobutyl)phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is(1-hydroxycyclobutyl)phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is (1-hydroxycyclobutyl)phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is (1-hydroxycyclobutyl)phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is(1-hydroxycyclobutyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is (1-hydroxycyclobutyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is (1-hydroxycyclobutyl)phenyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is(2-methyl-3-hydroxypropyl)phenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is(2-methyl-3-hydroxypropyl)phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is(2-methyl-3-hydroxypropyl)phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is(2-methyl-3-hydroxypropyl)phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is(2-methyl-3-hydroxypropyl)phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is (2-methyl-3-hydroxypropyl)phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is (2-methyl-3-hydroxypropyl)phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is(2-methyl-3-hydroxypropyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is (2-methyl-3-hydroxypropyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is (2-methyl-3-hydroxypropyl)phenyl.

In another embodiment A is —S(CH₂)₃S(CH₂)₂— and B is(1-hydroxy-2-phenylethyl)phenyl.

In another embodiment A is —(CH₂)₄OCH₂— and B is(1-hydroxy-2-phenylethyl)phenyl.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂— and B is(1-hydroxy-2-phenylethyl)phenyl.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂— and B is(1-hydroxy-2-phenylethyl)phenyl.

In another embodiment A is —(CH₂)₂S(CH₂)₃— and B is(1-hydroxy-2-phenylethyl)phenyl.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,and B is (1-hydroxy-2-phenylethyl)phenyl.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene, and B is (1-hydroxy-2-phenylethyl)phenyl.

In another embodiment A is —CH₂—O—(CH₂)₄— and B is(1-hydroxy-2-phenylethyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene, and B is (1-hydroxy-2-phenylethyl)phenyl.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene, and B is (1-hydroxy-2-phenylethyl)phenyl.

Another embodiment comprises a compound selected from the groupconsisting of

-   5-[(S)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxy]-pentanoic    acid;-   3-[(S)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-benzoic    acid;-   5-[(S)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-furan-2-carboxylic    acid;-   5-[(S)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-thiophene-2-carboxylic    acid;-   7-[(R)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-yl]-heptanoic    acid;-   5-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-carboxylic    acid;-   5-{(S)-1-[4-(1-Hydroxy-2-methyl-propyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-carboxylic    acid;-   5-{(S)-1-[4-(1-Hydroxy-2-phenyl-ethyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-carboxylic    acid; and-   5-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid.

The compounds of disclosed herein are useful for the prevention ortreatment of glaucoma or ocular hypertension in mammals, or for themanufacture of a medicament for the treatment of glaucoma or ocularhypertension. They are also useful for the treatment of those diseasesdisclosed in the art as being amenable to treatment by prostaglandin EP₂agonist, such as the ones listed previously.

A “pharmaceutically acceptable salt” is any salt that retains theactivity of the parent compound and does not impart any additionaldeleterious or untoward effects on the subject to which it isadministered and in the context in which it is administered compared tothe parent compound. A pharmaceutically acceptable salt also refers toany salt which may form in vivo as a result of administration of anacid, another salt, or a prodrug which is converted into an acid orsalt.

Pharmaceutically acceptable salts of acidic functional groups may bederived from organic or inorganic bases. The salt may comprise a mono orpolyvalent ion. Of particular interest are the inorganic ions, lithium,sodium, potassium, calcium, and magnesium. Organic salts may be madewith amines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Hydrochloric acid or some otherpharmaceutically acceptable acid may form a salt with a compound thatincludes a basic group, such as an amine or a pyridine ring.

A “prodrug” is a compound which is converted to a therapeutically activecompound after administration, and the term should be interpreted asbroadly herein as is generally understood in the art. While notintending to limit the scope of the invention, conversion may occur byhydrolysis of an ester group or some other biologically labile group.Generally, but not necessarily, a prodrug is inactive or less activethan the therapeutically active compound to which it is converted. Esterprodrugs of the compounds disclosed herein are specificallycontemplated. An ester may be derived from a carboxylic acid of C1 (i.e.the terminal carboxylic acid of a natural prostaglandin), or an estermay be derived from a carboxylic acid functional group on another partof the molecule, such as on a phenyl ring. While not intending to belimiting, an ester may be an alkyl ester, an aryl ester, or a heteroarylester. The term alkyl has the meaning generally understood by thoseskilled in the art and refers to linear, branched, or cyclic alkylmoieties. C₁₋₆ alkyl esters are particularly useful, where alkyl part ofthe ester has from 1 to 6 carbon atoms and includes, but is not limitedto, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,t-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and combinations thereof having from 1-6 carbonatoms, etc.

Those skilled in the art will readily understand that for administrationor the manufacture of medicaments the compounds disclosed herein can beadmixed with pharmaceutically acceptable excipients which per se arewell known in the art. Specifically, a drug to be administeredsystemically, it may be confected as a powder, pill, tablet or the like,or as a solution, emulsion, suspension, aerosol, syrup or elixirsuitable for oral or parenteral administration or inhalation.

For solid dosage forms or medicaments, non-toxic solid carriers include,but are not limited to, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, the polyalkylene glycols,talcum, cellulose, glucose, sucrose and magnesium carbonate. The soliddosage forms may be uncoated or they may be coated by known techniquesto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distcaratemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release. Liquid pharmaceuticallyadministrable dosage forms can, for example, comprise a solution orsuspension of one or more of the presently useful compounds and optionalpharmaceutical adjutants in a carrier, such as for example, water,saline, aqueous dextrose, glycerol, ethanol and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like. Typical examples of such auxiliary agentsare sodium acetate, sorbitan monolaurate, triethanolamine, sodiumacetate, triethanolamine oleate, etc. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in thisart; for example, see Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., 16th Edition, 1980. The composition ofthe formulation to be administered, in any event, contains a quantity ofone or more of the presently useful compounds in an amount effective toprovide the desired therapeutic effect.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol and the like. Inaddition, if desired, the injectable pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like.

The amount of the presently useful compound or compounds administeredis, of course, dependent on the therapeutic effect or effects desired,on the specific mammal being treated, on the severity and nature of themammal's condition, on the manner of administration, on the potency andpharmacodynamics of the particular compound or compounds employed, andon the judgment of the prescribing physician. The therapeuticallyeffective dosage of the presently useful compound or compounds ispreferably in the range of about 0.5 or about 1 to about 100 mg/kg/day.

A liquid which is ophthalmically acceptable is formulated such that itcan be administered topically to the eye. The comfort should bemaximized as much as possible, although sometimes formulationconsiderations (e.g. drug stability) may necessitate less than optimalcomfort. In the case that comfort cannot be maximized, the liquid shouldbe formulated such that the liquid is tolerable to the patient fortopical ophthalmic use. Additionally, an ophthalmically acceptableliquid should either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositions of thepresent invention include, but are not limited to, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations of the present invention. These vehicles include, but arenot limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl celluloseand purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative  0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10   pHadjustor q.s. pH 4.5-7.5 antioxidant as needed surfactant as neededpurified water as needed to make 100%

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,cosolvent, emulsifier, penetration enhancer, preservative system, andemollient.

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The compounds disclosed herein are also useful in combination with otherdrugs useful for the treatment of glaucoma or other conditions.

For the treatment of glaucoma, combination treatment with the followingclasses of drugs are contemplated:

-   β-Blockers (or β-adrenergic antagonists) including carteolol,    levobunolol, metiparanolol, timolol hemihydrate, timolol maleate,    β1-selective antagonists such as betaxolol, and the like, or    pharmaceutically acceptable salts or prodrugs thereof;-   Adrenergic Agonists including non-selective adrenergic agonists such    as epinephrine borate, epinephrine hydrochloride, and dipivefrin,    and the like, or pharmaceutically acceptable salts or prodrugs    thereof, and-   α₂-selective adrenergic agonists such as apraclonidine, brimonidine,    and the like, or pharmaceutically acceptable salts or prodrugs    thereof;-   Carbonic Anhydrase Inhibitors including acetazolamide,    dichlorphenamide, methazolamide, brinzolamide, dorzolamide, and the    like, or pharmaceutically acceptable salts or prodrugs thereof;-   Cholinergic Agonists including direct acting cholinergic agonists    such as carbachol, pilocarpine hydrochloride, pilocarbine nitrate,    pilocarpine, and the like, or pharmaceutically acceptable salts or    prodrugs thereof;-   cholinesterase inhibitors such as demecarium, echothiophate,    physostigmine, and the like, or pharmaceutically acceptable salts or    prodrugs thereof;-   Glutamate Antagonists and other neuroprotective agents such as Ca²⁺    channel blockers such as memantine, amantadine, rimantadine,    nitroglycerin, dextrophan, dextromethorphan, CGS-19755,    dihydropyridines, verapamil, emopamil, benzothiazepines, bepridil,    diphenylbutylpiperidines, diphenylpiperazines, HOE 166 and related    drugs, fluspirilene, eliprodil, ifenprodil, CP-101,606, tibalosine,    2309BT, and 840S, flunarizine, nicardipine, nifedimpine, nimodipine,    barnidipine, verapamil, lidoflazine, prenylamine lactate, amiloride,    and the like, or pharmaceutically acceptable salts or prodrugs    thereof;-   Prostamides such as bimatoprost, or pharmaceutically acceptable    salts or prodrugs thereof, and-   Prostaglandins including travoprost, UFO-21, chloprostenol,    fluprostenol, 13,14-dihydro-chloprostenol, isopropyl unoprostone,    latanoprost and the like.-   Cannabinoids including CB1 agonists such as WIN-55212-2 and CP-55940    and the like, or pharmaceutically acceptable salts or prodrugs    thereof.    For treatment of diseases affecting the eye including glaucoma,    these compounds can be administered topically, periocularly,    intraocularly, or by any other effective means known in the art.

Treatment of inflammatory bowel disease may be accomplished by theadministration of the compounds described herein to the sufferingmammal. Inflammatory bowel disease describes a variety of diseasescharacterized by inflammation of the bowels including, but not limitedto, ulcerative colitis and Crohn's disease. Treatment may beaccomplished by oral administration, by suppository, or parenteraladministration, or some other suitable method.

While not intending to limit the scope of the invention in any way,delivery of the compounds disclosed herein to the colon via oral dosageforms may be accomplished by any of a number of methods known in theart. For example, reviews by Chourasia and Jain in J Pharm PharmaceutSci 6 (1): 33-66, 2003 and Shareef et. al (AAPS PharmSci 2003; 5 (2)Article 17) describe a number of useful methods. While not intending tolimit the scope of the invention in any way these methods include 1)administration of a prodrug, including an azo or a carbohydrate basedprodrug; 2) coating the drug with, or encapsulating or impregnating thedrug into a polymer designed for delivery to the colon, 3) time releaseddelivery of the drug, 4) use of a bioadhesive system; and the like.

While not intending to be bound in any way by theory, it is believedthat intestinal microflora are capable of reductive cleavage of an azobond leaving the two nitrogen atoms as amine functional groups. Whilenot intending to limit the scope of the invention in any way, the azoprodrug approach has been used to deliver to 5-aminosalicylic acid tothe colons of humans in clinical trials for the treatment ofinflammatory bowel disease. It is also believed that bacteria of thelower GI also have enzymes which can digest glycosides, glucuronides,cyclodextrins, dextrans, and other carbohydrates, and ester prodrugsformed from these carbohydrates have been shown to deliver the parentactive drugs selectively to the colon. For example, in vivo and in vitrostudies on rats and guinea pigs with prodrugs of dexamethasone,prednisolone, hydrocortisone, and fludrocortisone, suggest thatglycoside conjugates may be useful for the delivery of steroids to thehuman colon. Other in vivo studies have suggested that glucouronide,cyclodextrin, and dextran prodrugs of steroids or non-steroidalanti-inflammatory drugs are useful for delivery of these drugs to thelower GI tract. An amide of salicylic acid and glutamic acid has beenshown to be useful for the delivery of salicylic acid to the colon ofrabbit and dog.

While not intending to limit the scope of the invention in any way,carbohydrate polymers such as amylase, arabinogalactan, chitosan,chondroiton sulfate, dextran, guar gum, pectin, xylin, and the like, orazo-group containing polymers can be used to coat a drug compound, or adrug may be impregnated or encapsulated in the polymer. It is believedthat after oral administration, the polymers remain stable in the upperGI tract, but are digested by the microflora of the lower GI thusreleasing the drug for treatment.

Polymers which are sensitive to pH may also be used since the colon hasa higher pH than the upper GI tract. Such polymers are commerciallyavailable. For example, Rohm Pharmaceuticals, Darmstadt, Germany,markets pH dependent methacrylate based polymers and copolymers whichhave varying solubilities over different pH ranges based upon the numberof free carboxylate groups in the polymer under the tradename Eudragit®.Several Eudragit® dosage forms are currently used to deliver salsalazinefor the treatment of ulcerative colitis and Crohn's disease. Timerelease systems, bioadhesive systems, and other delivery systems havealso been studied.

One embodiment is use of a compound in the manufacture of a medicamentfor the treatment of inflammatory bowel disease, said compoundcomprising

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O; and-   B is aryl or heteroaryl.

Another embodiment is use of a compound in the manufacture of amedicament for the treatment of inflammatory bowel disease, saidcompound comprising

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O; and-   B is phenyl.

Another embodiment is use of a compound in the manufacture of amedicament for the treatment of inflammatory bowel disease, saidcompound comprising

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O; and-   B is alkylphenyl.

Another embodiment is use of a compound in the manufacture of amedicament for the treatment of inflammatory bowel disease, saidcompound comprising

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O; and-   B is p-t-butylphenyl.

Another embodiment is use of a compound in the manufacture of amedicament for the treatment of inflammatory bowel disease, saidcompound of claim selected from the group consisting of

-   5-[(S)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxy]-pentanoic    acid;-   3-[(S)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-benzoic    acid;-   5-[(S)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-furan-2-carboxylic    acid;-   5-[(S)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-thiophene-2-carboxylic    acid;-   7-[(R)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-yl]-heptanoic    acid;-   5-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-carboxylic    acid;-   5-{(S)-1-[4-(1-Hydroxy-2-methyl-propyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-carboxylic    acid;-   5-{(S)-1-[4-(1-Hydroxy-2-phenyl-ethyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-carboxylic    acid;-   5-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid;-   5-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester;-   3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-benzoic    acid;-   5-{(S)-1-[4-(1-Hydroxy-pentyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid;-   5-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid;-   5-{(S)-1-[4-(1-Hydroxy-butyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid;-   5-{(S)-1-[4-(1-Hydroxy-propyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid;-   5-((E and    Z)-3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-allyl)-thiophene-2-carboxylic    acid;-   5-(3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid;-   5-(3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid isopropyl ester (mixture of diastereomers);-   5-{3-[(R)-1-(4-Hexanoyl-phenyl)-5-oxo-pyrrolidin-2-yl]-propyl}-thiophene-2-carboxylic    acid;-   5-[(S)-1-(4-Hexanoyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-thiophene-2-carboxylic    acid;-   5-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester (faster eluting diastereomer);-   5-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester (slower eluting diastereomer);-   5-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid (from faster eluting diastereomer);-   5-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid (from slower eluting diastereomer);-   5-(3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid methyl ester (faster eluting diastereomer);-   5-(3-{(R)-1-[4-(1-hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid methyl ester (slower eluting diastereomer);-   5-(3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid (from faster eluting diastereomer);-   5-(3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid (from slower eluting diastereomer);-   5-(3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid isopropyl ester (from faster eluting diastereomer);-   5-(3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid isopropyl ester (from slower eluting diastereomer);-   5-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester (mixture of diastereomers);-   5-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester (faster eluting diastereomer);-   5-{(S)-1-[4-(1-hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester (slower eluting diastereomer);-   5-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid (from faster eluting diastereomer);-   5-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid (from slower eluting diastereomer);-   5-(3-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid;-   5-(3-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid methyl ester (faster eluting diastereomer);-   5-(3-{(R)-1-[4-(1-hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid methyl ester (slower eluting diastereomer);-   5-(3-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid (from faster eluting diastereomer);-   5-(3-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid (from slower eluting diastereomer);-   5-(3-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid isopropyl ester (from faster eluting diastereomer);-   5-(3-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid isopropyl ester (from slower eluting diastereomer); and-   4-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxy}-benzoic    acid.

Another embodiment is use of a compound in the manufacture of amedicament for the treatment of inflammatory bowel disease, saidcompound of comprising

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—; and-   B is aryl or heteroaryl.

Another embodiment is use of a compound in the manufacture of amedicament for the treatment of inflammatory bowel disease, saidcompound of comprising

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—; and-   B is phenyl.

Another embodiment is use of a compound in the manufacture of amedicament for the treatment of inflammatory bowel disease, saidcompound of comprising

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—; and-   B is hydroxyalkylphenyl.

Another embodiment is use of a compound in the manufacture of amedicament for the treatment of inflammatory bowel disease, saidcompound comprising

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein a dashed line indicates the presence or absence of a bond;-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   R is hydrocarbyl or hydroxyhydrocarbyl having from 1 to 12 carbon    atoms;-   X is CH₂, O, or S; and-   G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—.

Another embodiment is use of a compound in the manufacture of amedicament for the treatment of inflammatory bowel disease, saidcompound comprising an N-aryl or N-heteroaryl gamma lactam which iseffective at reducing intraocular pressure in a mammal.

One embodiment is a compound comprising

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O; and-   B is aryl or heteroaryl.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O; and-   B is phenyl.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O; and-   B is alkylphenyl.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O; and-   B is p-t-butylphenyl.

Another embodiment is a compound of claim selected from the groupconsisting of

-   5-[(S)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxy]-pentanoic    acid;-   3-[(S)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-benzoic    acid;-   5-[(S)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-furan-2-carboxylic    acid;-   5-[(S)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-thiophene-2-carboxylic    acid;-   7-[(R)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-yl]-heptanoic    acid;-   5-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-carboxylic    acid;-   5-{(S)-1-[4-(1-Hydroxy-2-methyl-propyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-carboxylic    acid;-   5-{(S)-1-[4-(1-Hydroxy-2-phenyl-ethyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-carboxylic    acid;-   5-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid;-   5-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester;-   3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-benzoic    acid;-   5-{(S)-1-[4-(1-Hydroxy-pentyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid;-   5-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid;-   5-{(S)-1-[4-(1-Hydroxy-butyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid;-   5-{(S)-1-[4-(1-Hydroxy-propyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid;-   5-((E and    Z)-3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-allyl)-thiophene-2-carboxylic    acid;-   5-(3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid;-   5-(3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid isopropyl ester (mixture of diastereomers);-   5-{3-[(R)-1-(4-Hexanoyl-phenyl)-5-oxo-pyrrolidin-2-yl]-propyl}-thiophene-2-carboxylic    acid;-   5-[(S)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-thiophene-2-carboxylic    acid;-   5-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester (faster eluting diastereomer);-   5-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester (slower eluting diastereomer);-   5-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid (from faster eluting diastereomer);-   5-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid (from slower eluting diastereomer);-   5-(3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid methyl ester (faster eluting diastereomer);-   5-(3-{(R)-1-[4-(1-hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid methyl ester (slower eluting diastereomer);-   5-(3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid (from faster eluting diastereomer);-   5-(3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid (from slower eluting diastereomer);-   5-(3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid isopropyl ester (from faster eluting diastereomer);-   5-(3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid isopropyl ester (from slower eluting diastereomer);-   5-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester (mixture of diastereomers);-   5-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester (faster eluting diastereomer);-   5-{(S)-1-[4-(1-hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid isopropyl ester (slower eluting diastereomer);-   5-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid (from faster eluting diastereomer);-   5-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic    acid (from slower eluting diastereomer);-   5-(3-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid;-   5-(3-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid methyl ester (faster eluting diastereomer);-   5-(3-{(R)-1-[4-(1-hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid methyl ester (slower eluting diastereomer);-   5-(3-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid (from faster eluting diastereomer);-   5-(3-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid (from slower eluting diastereomer);-   5-(3-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid isopropyl ester (from faster eluting diastereomer);-   5-(3-{(R)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic    acid isopropyl ester (from slower eluting diastereomer); and

4-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxy}-benzoicacid. Another embodiment is a compound of comprising

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—; and-   B is aryl or heteroaryl.

Another embodiment is a compound of comprising

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—; and-   B is phenyl.

Another embodiment is a compound of comprising

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—; and-   B is hydroxyalkylphenyl.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein a dashed line indicates the presence or absence of a bond;-   Y is an organic acid functional group, or an amide or ester thereof    comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether    thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl    functional group;-   R is hydrocarbyl or hydroxyhydrocarbyl having from 1 to 12 carbon    atoms;-   X is CH₂, O, or S; and-   G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—.

Another embodiment is a compound comprising an N-aryl or N-heteroarylgamma lactam which is effective at reducing intraocular pressure in amammal.

Embodiments contemplated for each compound disclosed herein are use ofthe compound in the manufacture of a medicament for the treatment ofglaucoma or ocular hypertension.

Embodiments contemplated for each compound disclosed herein are use ofthe compound in the manufacture of a medicament for the treatment ofinflammatory bowel disease.

Embodiments contemplated for each compound disclosed herein are methodscomprising administering an effective amount of the compound to a mammalfor the treatment of glaucoma or ocular hypertension.

Embodiments contemplated for each compound disclosed herein are methodscomprising administering an effective amount of the compound to a mammalfor the treatment of inflammatory bowel disease.

Embodiments contemplated for each compound disclosed herein arecompositions comprising the compound, wherein said compositions areophthalmically acceptable liquids.

EXAMPLE 1

The compounds disclosed herein may be prepared from the compound shownbelow using the procedure described in U.S. Provisional PatentApplication No. 60/660,748, filed Mar. 10, 2005, the disclosure of whichis expressly incorporated by reference herein.

The compounds disclosed below are hypothetical examples of compoundwhich are useful as described herein. Each of these compounds, and saltsthereof, and prodrugs thereof, are specifically contemplated asindividual embodiments.

Running binding and activity studies on the hypothetical compounds aboveas described in U.S. Provisional Patent Application No. 60/660,748 woulddemonstrate that the compounds disclosed herein are selectiveprostaglandin EP₂ agonists, and are thus useful for the treatment ofglaucoma, ocular hypertension, inflammatory bowel disease, and the otherdiseases or conditions disclosed herein.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof,rather, the ambit of the present invention is to be governed only by thelawful construction of the appended claims.

1. A compound of the formula

or a pharmaceutically acceptable salt thereof; wherein Y is selectedfrom the group consisting of CO₂(R²), CON(R²)₂,CON(OR²)R²,CON(CH₂CH₂OH)₂, CONH(CH₂CH₂OH), CH₂OH, P(O)(OH)₂, CONHSO₂R², SO₂N(R²)₂,SO₂NHR², and tetrazolyl-R²; wherein R² is independently H, C₁-C₆ alkyl,phenyl, or biphenyl; A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be substituted with Sor O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene orheterointerarylene, the sum of m and o is from 1 to 4, and wherein oneCH₂ may be substituted with S or O; and B is aryl or heteroaryl, whereinaryl or heteroaryl may be substituted with one or more substituentsconsisting of from 1 to 12 non-hydrogen atoms and any necessary hydrogenatoms.
 2. The compound of claim 1 of the formula

or a pharmaceutically acceptable salt thereof; wherein G is1,3-interaryl or interheteroaryl, or —(CH₂)₃—.
 3. The compound of claim1, wherein B is substituted or unsubstituted phenyl.
 4. The compound ofclaim 2, wherein B is phenyl.
 5. The compound of claims 4, wherein B isalkylphenyl.
 6. The compound of claim 5, wherein B is p-t-butylphenyl.7. The compound of claim 4, wherein B is hydroxyalkylphenyl.
 8. Thecompound of claim 1 of the formula

or a pharmaceutically acceptable salt thereof, wherein R⁷ is linearalkyl having 3, 4, 5, 6 or 7 carbon atoms.
 9. The compound of claim 1 ofthe formula

or a pharmaceutically acceptable salt thereof; wherein a dashed lineindicates the presence or absence of a bond; R is hydrocarbyl orhydroxyhydrocarbyl having from 1 to 12 carbon atoms; X is CH₂, O, or S;and G is 1,3-interaryl or interheteroaryl, or —(CH₂)₃—.
 10. The compoundof claim 8 of the formula

or a pharmaceutically acceptable salt thereof, wherein X¹ and X² areindependently CH, O, or S; and R⁷ is linear alkyl having from 3 to 7carbon atoms.
 11. The compound of claim 8 of the formula

or a pharmaceutically acceptable salt thereof.
 12. The compound of claim11 of the formula

or a pharmaceutically acceptable salt thereof, wherein X¹ and X² areindependently CH, O, or S.
 13. A compound selected from the groupconsisting of 3-[(S)-1-(4-ted-B utyl-phenyl)-5-oxo-pyrrolid in-2-ylmethoxymethyl]-benzoic acid;3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-benzoic acid;4-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxy}-benzoic acid. 5-((E andZ)-3-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-allyl)-thiophene-2-carboxylicacid; 5-(3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic acid;5-(3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic acidmethyl ester;5-(3-{(R)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylicacid isopropyl ester; 5-[(S)-1-(4-Hexanoyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-thiophene-2-carboxylic acid;5-[(S)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolid in-2-ylmethoxy]-pentanoicacid; 5-[(S)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-furan-2-carboxylic acid;5-[(S)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-ylmethoxymethyl]-thiophene-2-carboxylic acid;5-{(S)-1-[4-(1-Hydroxy-2-methyl-propyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-arboxylicacid;5-{(S)-1-[4-(1-Hydroxy-2-phenyl-ethyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-arboxylicacid;5-{(S)-1-[4-(1-Hydroxy-butyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylicacid; 5-{(S)-1-[4-(1-Hydroxy-heptyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic acid isopropyl ester;5-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-furan-2-carboxylicacid;5-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylicacid; 5-{(S)-1-[4-(1-Hydroxy-hexyl)-phenyl]-5-oxo-pyrrolidin-2-ylmethoxymethyl}-thiophene-2-carboxylic acid isopropyl ester;5-{3-[(R)-1-(4-Hexanoyl-phenyl)-5-oxo-pyrrolidin-2-yl]-propyl}-thiophene-2-carboxylicacid; and7-[(R)-1-(4-tert-Butyl-phenyl)-5-oxo-pyrrolidin-2-yl]-heptanoic acid.14. A composition comprising a compound according to claim 1, whereinsaid composition is a liquid which is ophthalmically acceptable.
 15. Amethod of treating glaucoma or ocular hypertension comprisingadministering the compound of claim 1 to a mammal in need thereof.